Future Tools for Diagnosis and Monitoring mTBI

1. Future Tools for Diagnosis and Monitoring mTBI Maheen M. Adamson, PhD WRIISC Palo Alto VAHCS

2. Outline • TBI vs. mTBI • Dissecting the injury • Differences in structural MRI • Why is standard clinical intervention not enough? • Different types of neuroimaging that show promise.

3. Definition of mild TBI - review • Loss of consciousness (LOC) duration is relatively short: less than 1 minute versus less than 10 minutes vs less than 30 minutes • Post-traumatic amnesia (PTA) less than 24 hours • Glasgow Coma Scale (GCS) 13-15 (acutely) • No penetrating brain injury • No focal neurological findings • (different groups use different definitions)

4. Complicated Mild TBI • When clinical neuroimaging findings are present following a mTBI, the classification changes to “complicated mTBI,” which has a 6-month outcome more similar to moderate TBI1,2 1Williams DH, Levin HS, Eisenberg HM. Mild head injury classification. Neurosurgery 1990;27(3):422-8. 2Kashluba S, Hanks RA, Casey JE, Millis SR. Neuropsychologic and functional outcome after complicated mild traumatic brain injury. Arch Phys Med Rehabil 2008; 89(5): 904-11. From Belanger, 2009

5. What are the injuries? • Most Common Primary Injuries • Concussion (shaking of the brain caused by any violent blow the head, usually causing loss of consciousness) • Contusion (bruising) • Subdural hematoma (a bleed immediately under the dura) • Diffuse axonal injury • Most Common Secondary Injuries • Excitotoxicity (release of calcium, binding of magnesium) • Edema • Ischemia

6. Every Traumatic Brain Injury is Unique

7. Severity of TBI Cases Treated at DVBIC Sites

8. Military Issues regarding TBI • Soldiers in Iraq are being exposed to a large number of blasts (IEDs), many soldiers exposed at the same time • Some soldiers are exposed to many blasts • Soldiers wear body armor that protects vital organs • Helmets protect against missile injuries, but not against blast shock waves. • It is difficult to identify the brain changes with mild TBI • Consequently, many soldiers are getting brain damage and experiencing functional deficits attributable to TBI

9. What are the forces? Rotational force vector Translational force vector (Figure adapted from Arciniegas and Beresford 2001) Center of mass

10. TBI Pathology / Mechanisms • Coup-contra-coup – contusion • Collision of medial temporal lobe structures, orbito-frontal cortex with bones of base of skull • Breakage of blood vessels • Macro hemorrhages - injury to large blood vessels • Subdural hematoma – local pressure • Epidural hematoma – arterial pressure, rapidly progressing • Subarachnoid bleeding – herniation; normal pressure hydrocephalus • Small hemorrhages – arterioles (30-150 um) • Microbleeds at the gray-white matter junction • Disruption of blood flow, clotting • Local edema, increased intracranial pressure • Shear injury - breakage of axons (0.2 – 0.5 um) • Vulnerability at gray-white matter junctions (Not Diffuse??)

11. The Mechanisms of Damage from TBI ICP= Intracranial pressure CPP= Cerebral perfusion pressure SDH = Sub Dural Hematoma DAI = Diffuse Axonal Injury Courtesy Dr. Gary Abrams Maas et al, Lancet Neurology, 2008

12. Complex Interactions of Trauma Sequelae Courtesy Dr. Gary Abrams

13. Frontal and temporal pole contusions in two cases as reported by Gurdjian (1975). Note the extensiveness of the ventral surface contusions. From Impact head injury: Mechanistic, clinical and preventive correlation (pp. 242, 243), by E. S. Gurdjian, 1975, Springfield, IL: Charles C. Thomas.

14. Parasagittal plane through the long axis of the hippocampus at post-mortem. Note how the temporal pole is “cradled” and “hugged” by the middle cranial fossa as well as the sharp edge of the sphenoid ridge, asit juts into the Sylvian fissure. The head of hippocampus is approximately 2 cm from the sphenoid ridge and, when brain compression occurs, can deform over the ridge. From Atlas of the Human Brain (2nd ed., p. 83), by J. K. Mai, G. Paxinos, and J. K. Assheuer, 2004, Amsterdam: Elsevier.

15. Coronal views are presented on top from an older teenage patient who sustained a severe traumatic brain injury (TBI). As visualized, the fornix has withered in comparison to the age-matched control. This is thought to represent downstream degeneration of this structure as a result of the hippocampal and medial temporal lobe damage, including temporal horn dilation, that can be seen on the right in comparison with the control subject, where the true inversion recovery sequence MRI scan provides exquisite anatomical detail of the brain. Also, note the marked reduction in the size of the temporal stem and overall reduction in the amount and integrity of the temporal lobe white matter in comparison to the control. Adapted from Bigler, 2007

16. A patient who sustained a head injury from a fall, where the focal impact was to the back of the patient’s head, with the resulting contra coup injury to fronto-temporal regions. Axial CT toward the base of the skull depicting acute inferior frontal and anterior temporal lobe contusions, with associated edema. Note the close proximity of the contusions to the sphenoid. Adapted from Bigler, 2007

17. 3-D spiral CT coregistered with 3-D thin-slice MRI A middle-aged individual who sustained a significant temporal lobe contusion as a consequence of a high speed, side-impact MVA. This patient did sustain a significant left temporal lobe contusion, where the follow-up MRI approximately 2 years post-injury demonstrates significant temporal horn dilation, hippocampal atrophy (compare left and right hippocampal size), and general volume loss of the temporal lobe. Adapted from Bigler, 2007

18. Note variations in: Location Volume Depth Bigler, Neuropsychology, 2007

19. What does the future hold? • Arterial Spin Labeling Perfusion (clinical and research applications) • Susceptibility weighted imaging (enhanced contrast magnitude image which is exquisitely sensitive to venous blood, hemorrhage and iron storage) • Functional MRI (functional correlate of cognition) • Resting states of the brain

20. Arterial spin labeling perfusion Group activation maps obtained during letter 2-back working memory task from control subjects (left)and patients with traumatic brain injury studied following either placebo (middle) or methylphenidate (MPH) (right). Frontal activation in patients is reduced on placebo when compared with activation in controls, but normal-appearing activation is restored after MPH administration. Source: Unpublished data courtesy of Junghoon Kim and John Whyte, Moss Rehabilitation Institute.

21. Susceptibility Weighted Imaging (SWI) Regions of venous vascular content and hemorrhage in a tumor, which are not seen in the conventional postcontrast T1-weighted image (left) (Sehgal et al., 2005).

22. Functional MRI

23. Working Memory in mTBI McAllister et al., 2001

24. Longitudinal Functional MRI in Severe TBI • Increased activation observed after 6-month evolution in TBI patients during the 3-back condition. • The most striking changes were seen in the bilateral prefrontal cortex, with left hemisphere predominance. • The second region that showed statistical significant changes was the bilateral parietal posterior region. • Both regions are involved in working memory processes. Statistical Parametric Maps with left as left.

25. Kim et al., 2009

26. Conventional MRI and resting-state fMRI correlation analysis in a 21-year-old with verbal memory deficits following traumatic brain injury (A) Conventional MRI (FLAIR) revealed bilateral superior frontal lesions but no abnormalities that would explain the patient’s verbal memory deficit (left to right: transverse slices at the level of hippocampus, thalamus, fornix, cingulum). MacDonald et al., 2008

27. Resting state fMRI Spatial map of resting BOLD correlations with the left hippocampus. Yellow arrows indicate absence of significant correlations between the left hippocampus and anterior cingulate or between left hippocampus and anterior thalamus. White arrows point to areas of abnormally increased correlation with the left hippocampus, of unknown importance. (C) Normal right hippocampal functional connectivity. Top panel: BOLD signal time course in the right hippocampus (green line) and anterior cingulate (blue line) were normally correlated (r 0.40). Bottom panel: spatial map of resting BOLD correlations with right hippocampus. Significant correlations were observed between the right hippocampus and anterior cingulate as well as anterior thalamus (yellow arrows). Images displayed in anatomic space; patient’s left side on the left side of the images. MacDonald et al., 2008

28. Conclusions • High resolution MRI • PET Amyloid imaging • Separating PTSD from TBI • Understanding the long term effects of mTBI in OEF/OIF population in the context of neural, behavior and cognitive changes